GB-2247680 discloses pregna-1,4-diene-3,20-dione-16-17-acetal-21 esters and their use in the treatment of inflammatory conditions.
The compounds have the general structure: ##STR2## wherein R.sub.1 is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R.sub.2 is acetyl or isobutanoyl.
Ciclesonide is 11.beta., 16.alpha., 17, 21-tetrahydroxypregna 1,4-diene-3,20-dione, cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyrate having the structure of formula (I) without fluorine atoms and in which R.sub.1 is cyclohexyl and R.sub.2 is isobutanoyl. This compound has undergone evaluation as an antiasthmatic and pharmacokinetic studies show that it will be useful in an inhaler formulation. Ciclesonide is only moderately absorbed after oral administration and has low systemic activity. Concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. Systemic activity of ciclesonide is three times lower than that of budes onide but anti-inflammatory activity is higher for the former.
GB-2247680 proposes a specific pressurized aerosol formulation for delivering ciclesonide for oral and nasal inhalation. The disclosed formulation consists of ciclesonide as a micronized suspension of particles, sorbitan trioleate surfactant, and a mixture of three CFC propellants: trichloro-fluoromethane, dichlorotetrafluoromethane, and dichlorodifluoromethane. However these CFC propellants are now believed to provoke the degradation of stratospheric ozone and there is a need to provide aerosol formulations for medicaments which employ so-called "ozone-friendly" propellants.
A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise hydrofluorocarbons and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777, W091/04011, W091/11173, W091/11495, W091/14422, W093/11743, and EP-0553298 (all hereby incorporated by reference). These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome problems associated with the use of this new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. The applications propose, for example, the addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc.).
However, despite the various approaches used in formulating drugs for use in aerosol inhalation, there are still many serious difficulties and uncertainties often encountered in attempting to develop a physically and chemically stable CFC-free formulation that reliably delivers an accurate dose of drug having the proper particle size range. In particular, there is a need for a CFC-free medicinal aerosol product containing ciclesonide (or similar molecules) that is chemically and physically stable and that is suitable for delivery to the respiratory system of a patient.